Inborn Errors of Metabolism (proteins and lipid synthesis)

Question 1

Cause of inborn errors in metabolism

Answer 1

genetic, mostly involve single gene

Question 2

Clinical presentation of IEMs usually due to?

Answer 2

accumulation of toxic substance or deficiency of a product

Question 3

Timing of presentation of IEMs

Answer 3

at any age

Question 4

What does the clinical presentation of IEMs depend on?

Answer 4

• timing depends on: level of accumulation of toxic products, deficiency of product
• onset and severity depends on: diet and intercurrent illness

Question 5

Presentation of disorders of carbohydrate or protein metabolism and energy production tend to:

Answer 5

• present in neonatal period or early infancy
• be unrelenting and rapidly progressive
• less severe variants usually present later

Question 6

Presentation of fatty acid oxidation, glycogen storage, and lysosomal storage disorders tend to:

Answer 6

• present in infancy or childhood with subtle neurological or psychiatric features
• often undiagnosed until adulthood

Question 7

What is the rationale for newborn screening?

Answer 7

• heel prick test @ 3-5 days old
• allows for early detection–> early treatment–> better clinical outcome
• reduces morbidity and premature mortality

Question 8

Classifications of IEMs:

Answer 8

-Group 1: disorders causing intoxication
-Group 2: disorders of energy metabolism
Group 3: disorders involving complex molecules

Question 9

Features of Group 1 IEMs:

Answer 9

• do not interfere with embryo-fetal development
• present after a symptom free interval
• clinical signs of intoxication may be acute or chronic
• most are treatable by removal of toxin

Question 10

Acute vs chronic clinical signs of intoxication

Answer 10

• acute: vomiting, coma, liver failure

- chronic: failure to thrive, developmental delay, ectopic lentis (dislocation of lens)

Question 11

Disorders that give rise to intoxication:

Answer 11

• amino acidopathies (phenylketonuria, maple syrup urine disease, homocystinuria, tyrosinaemias)
• organic acidurias (methylmalonic aciduria, propionic aciduria, glutaric aciduria type I)
• urea cycle disorders (ornithine transcarbamylase (OTC) deficiency, citrullinaemia)
• sugar intolerances (classic galactosaemia, hereditary fructose intolerance)
• metal intoxication (Wilson’s disease, Menkes disease, haemochromatosis)
• porphyrias

Question 12

Hyperphenylalaninaemia: genetics, diagnosis, clinical symptoms if not detected, management

Answer 12

• Genetics: autosomal recessive
• Diagnosis: newborn screen (heel prick) test, biochemical (amino acid analysis)
• Clinical symptoms: irritability, vomiting, seizures, mental retardation by 4-6 months, reduced melanin production (pale, fair hair, blue eyes), frequently generalized eczema
• Management: diet low in phenylalanine (supplemented with tyrosine), cofactor related form (neurotransmitter supplementation)

Question 13

Tyrosinaemia Type I (defect, biochemistry, symptoms, treatment)

Answer 13

• Defect: deficiency in fumarylacetoacetate hydrolase
• Biochemistry: accumulation of fumaryl acetoacetate and its metabolites in urine (particularly succinyl acetone)
• Symptoms: characteristic cabbage like odor, liver failure and renal tubular acidosis
• Treatment: dietary restriction of Phe and Tyr, Drug: nitisinone

Question 14

What are the clinical manifestations of alkaptonuria?

Answer 14

• dark urine
• pigmentation phenotyle called ochronosis (pigmentation of ears and eyes)
• arthritis associated with calcification of joints

Question 15

Maple Syrup Urine Disease (defect, biochemistry, symptoms, treatment)

Answer 15

-defect: metabolism of leucine, isoleucine and valine (deficiency in alpha-keto acid dehydrogenase)
-biochemistry: alpha-amino acids and their alpha-keto analogs (elevated in plasma and urine)
-Symptoms: normal first few days of life, progressive lethargy, weight loss, episodes of hypertonia and hypotonia, maple syrup urine odor, ketosis coma and death if not treated
-Treatment: dietary restriction of branched chain amino acids
-

Question 16

Homocystinuria

Answer 16

• defect in cystathionine synthase
• accumulation of homocysteine in urine
• methionine and other metabolites elevated in blood
• cardiovascular disease, deep vein thrombosis and stroke, mental retardation, osteoporosis, dislocation of the lens

Question 17

What are the dibasic amino acids?

Answer 17

COAL (cysteine, ornithine, arginine, lysine)

Question 18

Mechanism of action of cystinuria

Answer 18

disorder of the proximal tubule’s reabsorption of filtered cysteine and dibasic amino acids leading to accumulation and precipitation of stones of cystine in the urinary tract

Question 19

What do disorders of amino acid transport cause?

Answer 19

defects cause aminoaciduria (amino acids in urine)

Question 20

Examples of disorders of amino acid transport

Answer 20

• cystinuria (cystine and dibasic amino acids)
• lysinuric protein intolerance (LPI) (dibasic amino acids)
• Hartnup disease: renal and intestinal transport defect (neutral and branched amino acids)
• Iminoglycinuria: may be transient in premature newborns (proline, hydroxyproline and glycine renal tubular transport defect)

Question 21

Cystinuria (clinical presentation, defect, biochemistry, treatment)

Answer 21

-Clinical presentation: cystine renal stones
-Defect: defective absorption of cystine and dibasic amino acids (proximal renal tubules and small intestine)
-Biochemistry (dibasic AA in urine are elevated, AA in plasma normal)
Treatment: high fluid intake (24hrs), alkalinisation of urine with sodium bicarbonate

Question 22

Lysinuric protein intolerance (clinical presentation, defect, biochemistry, treatment)

Answer 22

• Clinical presentation: failure to thrive, poor appetite, protein aversion, hyperammonaemia w/ progressive encephalopathy, renal failure, osteoporosis)
• Defect: absorption of dibasic amino acids (Lys, Arg, Orn)–impaired function of urea cycle and lysine deficiency
• Biochemistry: plasma (elev. NH3), AA plamsa (reduced Arg, Lys, Orn), AA in urine (elev. Arg, Lys, Orn)
• Treatment: protein restriction with citrulline replacement to enhance Urea cycle

Question 23

Hyperammonaemia (characterization, signs of intoxication)

Answer 23

• characterized by high levels of ammonia in the blood

- tremors, slurred speech, somnolence, vomiting, cerebral edema and blurred vision (ammonia neurotoxic to CNS)

Question 24

Causes of hyperammonaemia

Answer 24

• Acquired: liver insufficiency, transient hyperammonaemia of the newborn (THAN)
• Congenital: urea cycle disorders, transport defects of urea cycle intermediates

Question 25

Organic Aciduria (biochemistry and genetics)

Answer 25

• group of disorders that cause accumulation of organic acids in blood and urine
• autosomal recessive

Question 26

Describe organic acids

Answer 26

• include carboxylic acids, with or w/out keto, hydroxyl or other non-amino functional groups
• common features–water soluble, acids and ninhydrin stain negative (No N group)
• derived from dietary protein, fat and carbs

Question 27

Glutaric Aciduria Type I (GA1): defect, biochemistry, symptoms, treatment

Answer 27

• Defect: metabolism of lysine, hydroxylysine and tryptophan (deficiency in glutaryl CoA dehydrogenase)
• Biochemistry: harmful organic acid accumulation
• Symptoms: dystonia, dyskinesia, excretion of glutaric and 3 hydroxy glutaric acids in urine, neuronal degeneration, seizures (untreated leads to brain damage and possibly death)
• Treatment: dietary restriction of protein, carnitine

Question 28

Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency (MCADD): description, symptoms

Answer 28

• disorder of FA oxidation–> impaired breakdown of medium chain FAs into acetyl-coA
• symptoms: hypoketotic hypoglycemia, liver dysfunction, SID, lethargy, seizures and coma, intolerance to fasting

Question 29

What is MCAD responsible for?

Answer 29

for the dehydrogenation step of fatty acids with chain lengths between 6-12 carbons as they undergo beta-oxidation in the mitochondria

Question 30

What does beta-oxidation of long chain fatty caids produce?

Answer 30

two carbon units, acetyl-coA and the reducing equivalents NADH and FADH2